Single-cell long-read targeted sequencing reveals transcriptional variation in ovarian cancer.

Single-cell RNA sequencing predominantly employs short-read sequencing to characterize cell types, states and dynamics; however, it is inadequate for comprehensive characterization of RNA isoforms. Long-read sequencing technologies enable single-cell RNA isoform detection but are hampered by lower throughput and unintended sequencing of artifacts. Here we develop Single-cell Targeted Isoform Long-Read Sequencing (scTaILoR-seq), a hybridization capture method which targets over a thousand genes of interest, improving the median number of on-target transcripts per cell by 29-fold. We use scTaILoR-seq to identify and quantify RNA isoforms from ovarian cancer cell lines and primary tumors, yielding 10,796 single-cell transcriptomes. Using long-read variant calling we reveal associations of expressed single nucleotide variants (SNVs) with alternative transcript structures. Phasing of SNVs across transcripts enables the measurement of allelic imbalance within distinct cell populations. Overall, scTaILoR-seq is a long-read targeted RNA sequencing method and analytical framework for exploring transcriptional variation at single-cell resolution.

Combatant Command Medical Entry Standards.

INTRODUCTION: The medical entry standards for the United States Central Command (USCENTCOM) restrict individuals with various medical conditions from entering the deployed environment. The impact of this program is unknown. MATERIALS AND METHODS: The total number of army personnel deployed to USCENTCOM, the number of individuals with a medical entry waiver adjudicated by United States Army Central (USARCENT), and the evacuation number for each population were compared for calendar year 2023 (CY2023). RESULTS: A total estimated population of 20,519 U.S. Army personnel were deployed to USCENTCOM. A population of 1,918 received a medical entry waiver due to a disqualifying medical condition. The evacuation rate for the general population was 2.4% compared to the 1.4% evacuation rate of the population with a medical entry waiver (P = .0027). CONCLUSION: The medical entry standards, as written and adjudicated in 2023, resulted in a relatively reduced evacuation rate for individuals with otherwise prohibited medical conditions compared to the general deployed population.

Isolated Immune Checkpoint Inhibitor-Induced Gastritis Leading to Gastrocolic Fistula Formation.

Immune checkpoint inhibitors (ICIs) are important immunotherapeutic tools with known potential for adverse events (immune-related adverse events [irAEs]) in the gastrointestinal system. Although ICI-induced colitis and diarrhea are well documented, irAEs localized to the stomach are less frequently described. The management of most irAEs is suspension of ICI therapy and immune suppression. In rare cases of ICI-induced gastritis, treatment strategies of immune suppression have been scarcely described. To our knowledge, there have been no reported cases of severe ICI-induced gastritis leading to fistula formation. This case report describes a patient with isolated ICI-induced gastritis leading to an ulcer with gastrocolic fistula and his treatment course.

Outcomes of Single Anastomosis Sleeve Ileal (SASI) Bypass as an Alternative Procedure in Treating Obesity: An Updated Systematic Review and Meta-Analysis.

PURPOSE: The Single Anastomosis Sleeve Ileal (SASI) bypass is a novel bariatric procedure that simplifies Santoro's procedure, balancing functional restriction and neuroendocrine modulation while preserving anatomy. We aim to conduct a single-arm meta-analysis of the SASI bypass to explore its moderate-term efficacy, as this might expand the available choices for surgeons to choose the best bariatric surgery that suits the patient's condition. MATERIALS AND METHODS: We conducted a comprehensive search on PubMed, Scopus, EMBASE, and Cochrane to identify studies for the SASI bypass surgery focusing on outcomes such as %EWL, %TWL, remission rate of comorbidities, and complications. The statistical analysis was carried out using RStudio version 4.3.2. Heterogeneity was assessed using the Cochrane Q test and I2 statistics. RESULTS: Our findings illuminate SASI's potency by undertaking a single-arm meta-analysis involving 1873 patients across 26 studies. At 12 months, we report a noteworthy % Excess Weight Loss (%EWL) (Mean 84.13; 95% CI 78.41-89.85; I2 = 95%), and % Total Weight Loss (%TWL) (Mean 35.17; 95% CI 32.30-38.04; I2 = 97%), highlighting SASI's efficacy on weight loss. Cumulative meta-analyses supported these findings. More weight loss was observed with a 250 cm common limb and a greater than 3 cm anastomosis. An 88.28% remission rate in type 2 diabetes mellitus (95% CI 79.74-95.03; I2 = 84%) at 12 months was observed. Beyond weight outcomes, SASI impacts comorbidities with a good safety profile. CONCLUSION: Our study positions the SASI bypass as a good alternative option. However, long-term efficacy is yet to be explored in the future.

Safety and Efficacy of Barbed Sutures Compared to Non-barbed Sutures in Bariatric Surgery: An Updated Systematic Review and Meta-analysis.

PURPOSE: Mastering intracorporeal suturing is challenging in the evolution from conventional to laparoscopic bariatric surgery. Among various techniques competing for superiority in overcoming this hurdle, we focus on exploring the potential of barbed sutures through a meta-analysis that compares outcomes to those of conventional non-barbed sutures in bariatric surgery. MATERIALS AND METHODS: We conducted a comprehensive search on PubMed, Scopus, and Embase to identify studies comparing barbed sutures with non-barbed sutures in bariatric surgeries, focusing on outcomes such as operative time, suturing time, postoperative complications, and hospital stay. The statistical analysis was carried out using RStudio version 4.3.2. Heterogeneity was assessed using the Cochrane Q test and I2 statistics. RESULTS: Incorporating data from 11 studies involving a total of 27,442 patients, including 3,516 in the barbed suture group across various bariatric surgeries, our analysis demonstrates a significant reduction in suturing time (mean difference -4.87; 95% CI -8.43 to -1.30; p < 0.01; I2 = 99%) associated with the use of barbed sutures. Specifically, in Roux-en-Y gastric bypass, we observed a significant decrease in operative time (mean difference -12.11; 95% CI -19.27 to -4.95; p < 0.01; I2 = 93%). Subgroup analyses and leave-one-out analyses consistently supported these findings. Furthermore, we found that the mean body mass index did not significantly predict the mean difference in operative time outcome. No significant differences emerged in hospital stay or postoperative complications, including leak, bleeding, stenosis, and bowel obstruction (p > 0.05). CONCLUSION: Our study findings address barbed sutures as a potential alternative for laparoscopic intracorporeal suturing in bariatric surgery.

Evolving trends in immunosuppression use and cytomegalovirus infection risk over the past decade in kidney transplantation.

BACKGROUND: The goal was to determine trends in immunosuppression use and its impact on cytomegalovirus (CMV) outcomes over the past 10 years. METHODS: This was a single-center longitudinal cohort study of adult kidney recipients transplanted between Jan 2012 and June 2021. Baseline and follow-up data were gathered via chart abstraction and analyzed using univariate and multivariate analyses. RESULTS: Of 2392 kidney transplants conducted, 131 patients did not meet inclusion criteria. The mean age was 52 years, 41% were female, 57% were black, and 19% were CMV high-risk. The use of rabbit anti-thymocyte globulin (RATG) induction (odds ratio [OR] 1.6, 1.3-2.1), tacrolimus (FK) level >8 ng/mL (OR 1.1, 1.09-1.11), CMV D+/R- rates (OR 1.06, 1.02-1.10), white blood cell count <3000 (OR 1.22, 1.18-1.26) and valganciclovir prophylaxis (OR 1.7, 1.6-1.9) have significantly increased over the past 10 years.  Rejection rates (OR 0.86, 0.82-0.91) and BK viremia >2000 (OR 0.91, 0.91-0.98) have decreased. RATG induction (adjusted hazard ratio [aHR] 1.35, 1.2-1.5), FK >8 ng/mL (aHR 3.5, 3.2-3.9), Belatacept conversion (aHR 2.5, 2.1-3.1), and rejection (aHR 1.8, 1.6-2.0) were significant risk factors for developing CMV infection, while mycophenolate mofetil <1500 mg (aHR 0.52, 0.47-0.59), mammalian target of rapamycin inhibitor (mTORi) conversion (0.77, 0.56-0.89), cyclosporine-A conversion (aHR 0.68, 0.56-0.84) were associated with lower risk of CMV infection. CONCLUSION: Increasing use of potent immunosuppression coupled with higher CMV D+/R- F rates may be driving higher rates of CMV infection. Cyclosporine and mTORi conversion appears to be protective against CMV.  A more individualized immunosuppression regimen based on infection risk merits consideration.

Safety and Technical Efficacy of Pediatric Brainstem Biopsies: An Updated Meta-Analysis of 1000+ Children.

BACKGROUND: Brainstem tumors represent ∼10% of pediatric brain tumors, ∼80% of these are diffuse midline glioma. Given invariably poor prognosis in diffuse midline glioma, there continues to be immense variation worldwide in performing biopsy of these lesions. Several contemporary studies in recent years have provided new data to elucidate the safety profile of biopsy and an updated meta-analysis is thus indicated. METHODS: We found 29 studies of pediatric brainstem biopsy in the last 20 years (2003-2023, 1002 children). We applied meta-analysis of proportions using a random-effects model to generate point estimates, confidence intervals, and measures of heterogeneity. RESULTS: Eighty-seven percent of procedures were stereotactic needle biopsies (of these, 62% with a frame, 14% without frame, and 24% robotic.) Biopsy resulted in a histological diagnosis ("technical yield") in 96.8% of cases (95% CI 95.4-98.2). Temporary complications were seen in 6% (95 CI 4-8), with the most common neurological complications being 1) cranial nerve dysfunction, 2) worsening or new ataxia, and 3) limb weakness. Permanent complications (excluding death) were seen in 1% (95% CI 0.5-2), most commonly including cranial nerve dysfunction and limb weakness. Five deaths were reported in the entire pooled cohort of 1002 children (0.5%). CONCLUSIONS: When counseling families on the merits of brainstem biopsy in children, it is reasonable to state that permanent morbidity is rare (<2%). If biopsy is performed specifically to facilitate enrollment in clinical trials requiring a molecular diagnosis, the risks of biopsy outlined here should be weighed against potential benefits of trial enrollment.

While You Are Sleeping: Marital Ambivalence and Blunted Nocturnal Blood Pressure.

Marital relationships offer health benefits, including a lower risk of cardiovascular disease (CVD). However, quality of the relationship matters; ambivalent behaviors may increase CVD risk by affecting blunted nocturnal blood pressure (BP) dipping. This study tracked daytime and nocturnal SBP and DBP in 180 normotensive individuals (90 couples; participant mean age 25.04; 91.58% white) over a 24 h period using ambulatory blood pressure monitors to explore the impact of martial quality. Results showed that perceptions of spousal ambivalence were associated with blunted nocturnal BP dipping. Perceptions of one's own behavior as ambivalent also showed blunted nocturnal dipping. When in an ambivalent relationship, a gender interaction was found such that women were most likely to have blunted SBP dipping, but men were more likely to have blunted nocturnal DBP dipping. Overall, this study found an association between ambivalence and BP dipping, thus uncovering one virtually unexplored pathway by which marital relationships may have adverse effects on health.

Analysis of leadership and team management skills of middle-level healthcare managers of Valsad district, Gujarat.

Background: The healthcare managers need to develop the managerial skills and use it for better healthcare delivery. A manager requires leadership skill to empower employees and motivate them to work in an efficient manner to achieve organizational goal. Motivating employees/subordinates and developing positive attitude toward them is one of the crucial skills that the leader needs to develop. The way health team works as a unit affects the outcome and needs good leader. With this background, the current study tends to explore the managerial skills of middle-level managers. Objectives: 1. To assess the leadership and team management skills of middle-level managers and 2. To find out motivational factors used by managers. Materials and Methods: A cross-sectional study was conducted among district-level healthcare managers and medical officers. Data collection was performed via semistructured and scale-based questionnaire and analyzed using Microsoft office excel. Results: 60% of managers had participative leadership style. Team work skills were fair enough among the managers. 53% of medical officers were freshly appointed with experience of less than one year. The middle-level managers used appreciation of work (41.8%) as major motivator of the team. Conclusions: The middle-level healthcare managers have good leadership quality as well as teamwork skills. Appreciation of work is commonly used motivator.

Pediatric Endocrine Society Statement on Considerations for Use of Teplizumab (Tzield™) in Clinical Practice.

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at T-cell marker CD3, is the first medication approved by the FDA to delay progression from stage 2 to stage 3 type 1 diabetes. To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance on the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration, and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab.

Guidelines for Performing a Comprehensive Pediatric Transthoracic Echocardiogram: Recommendations From the American Society of Echocardiography.

Echocardiography is a fundamental component of pediatric cardiology, and appropriate indications have been established for its use in the setting of suspected, congenital, or acquired heart disease in children. Since the publication of guidelines for pediatric transthoracic echocardiography in 2006 and 2010, advances in knowledge and technology have expanded the scope of practice beyond the use of traditional modalities such as two-dimensional, M-mode, and Doppler echocardiography to evaluate the cardiac segmental structures and their function. Adjunct modalities such as contrast, three-dimensional, and speckle-tracking echocardiography are now used routinely at many pediatric centers. Guidelines and recommendations for the use of traditional and newer adjunct modalities in children are described in detail in this document. In addition, suggested protocols related to standard operations, infection control, sedation, and quality assurance and improvement are included to provide an organizational structure for centers performing pediatric transthoracic echocardiograms.

Safety and Efficacy of Direct Oral Anticoagulant in Addition to Antiplatelet Therapy After Acute Coronary Syndrome: A Systemic Review and Meta-analysis of 53,869 Patients.

INTRODUCTION: Significant progress has been made in the management of patients with acute coronary syndrome (ACS) during the past few decades. However, the role of direct oral anticoagulants (DOACs) in post-ACS prophylactic therapy remains unknown. This study aims to assess the efficacy and safety of DOACs plus antiplatelet treatment (APT) after ACS. METHODS: A systematic literature search was conducted to identify randomized clinical trials comparing DOACs plus APT with APT alone after ACS. The primary efficacy end points were cardiovascular mortality, myocardial infarction, all-cause mortality, and stroke and systemic embolization (SSE). The primary safety end point was major bleeding. The random-effects model was used to calculate relative risk (RR) and corresponding 95% CIs. RESULTS: Nine trials with a total of 53,869 patients were identified, with 33,011 (61.2%) in the DOACs plus APT group and 20,858 (38.8%) in the APT alone group. The use of DOACs did not decrease the risk of cardiovascular death (RR = 0.87; 95% CI, 0.75-1.01; P = 0.08; I2 = 0%) or myocardial infarction (RR = 0.90; 95% CI, 0.80-1.02; P = 0.10; I2 = 6%). However, the risk of SSE was significantly lower in patients who received DOACs plus APT compared with APT alone (RR = 0.67; 95% CI, 0.50-0.90; P = 0.008). Moreover, all-cause mortality was significantly lower in the DOACs plus APT group (RR = 0.83; 95% CI, 0.71-98; P = 0.03; I2 = 0%). However, the risk of major bleeding was significantly higher in patients treated with DOACs plus APT compared with APT alone (RR = 2.53; 95% CI, 1.96-3.26; P < 0.01; I2 = 0%), as was the risk of nonmajor bleeding (RR = 2.27; 95% CI, 1.51-3.41; P < 0.01). IMPLICATIONS: DOACs plus APT for the prevention of left ventricular thrombus in patients with ACS were associated with a lower risk of SSE and all-cause mortality but increased the risk of major and nonmajor bleeding. The benefits and risks of this approach should be weighed based on a patient's individual clinical characteristics.

Kenya's experience implementing event-based surveillance during the COVID-19 pandemic.

Event-based surveillance (EBS) can be implemented in most settings for the detection of potential health threats by recognition and immediate reporting of predefined signals. Such a system complements existing case-based and sentinel surveillance systems. With the emergence of the COVID-19 pandemic in early 2020, the Kenya Ministry of Health (MOH) modified and expanded an EBS system in both community and health facility settings for the reporting of COVID-19-related signals. Using an electronic reporting tool, m-Dharura, MOH recorded 8790 signals reported, with 3002 (34.2%) verified as events, across both community and health facility sites from March 2020 to June 2021. A subsequent evaluation found that the EBS system was flexible enough to incorporate the addition of COVID-19-related signals during a pandemic and maintain high rates of reporting from participants. Inadequate resources for follow-up investigations to reported events, lack of supportive supervision for some community health volunteers and lack of data system interoperability were identified as challenges to be addressed as the EBS system in Kenya continues to expand to additional jurisdictions.

Impact of obesity on the conversion of immediate-release tacrolimus to extended-release tacrolimus in kidney transplant recipients.

Outcomes analyzing conversion from IR-tacrolimus (IR) to LCP-tacrolimus (LCP) in obesity are limited. This was a retrospective longitudinal cohort study of patients converted from IR to LCP from June 2019 to October 2020. Primary outcomes were conversion ratios for weight-based dose at a steady-state therapeutic level and identification of appropriate dosing weight. Other outcomes included tacrolimus coefficient of variation (CV), time in therapeutic range (TITR), adverse events, infections, donor specific antibodies (DSAs), and acute rejection. A total of 292 patients were included; 156 and 136 patients with a BMI < 30 and BMI ≥ 30 kg/m2 , respectively. Baseline characteristics were similar, except for pancreas transplant, diabetes, and HLA mismatch. IR to LCP conversion ratio ranged from .73 to .79. Mean LCP dose was similar (.08 vs. .07 mg/kg/day for BMI < 30 and BMI ≥ 30 kg/m2 , respectively); there was a significant difference in IR and LCP mg/kg dosing at steady state with TBW (.11 mg/kg vs.09 mg/kg and .08 mg/kg vs. .06 mg/kg, respectively). The most appropriate dosing weight was adjusted body weight (AdjBW), consistent across IR and LCP steady-state doses, and might yield more accurate steady-state dosing requirements. In multivariable modeling, BMI was a significant predictor of steady state mg/kg dosing at therapeutic goal for total body weight (TBW), but not ideal body weight (IBW) or AdjBW.

Body Mass Index and Outcomes of Transcatheter Aortic Valve Replacement: A Retrospective Observational Study.

The influence of body mass index (BMI) on Transcatheter Aortic Valve Replacement (TAVR) outcomes has been the focus of several previous studies. In this study, we examined the relationship between BMI and various clinical outcomes following TAVR procedures. A comprehensive analysis was conducted using a large cohort of patients who underwent TAVR. In this study, we identified patients who underwent Transcatheter aortic valve replacement (TAVR) in the year 2020. Procedure Classification System (ICD-10-PCS) codes were used to identify TAVR cases. The weighted final study sample included 77319 TAVR hospitalizations. Patients were categorized into 5 groups based on their Body Mass Index (BMI. Our findings revealed that there was no significant difference in in-hospital mortality among different BMI groups when compared to patients with a normal BMI (20 to 24.9). patients with a BMI of 25 or higher demonstrated a statistically significant shorter duration of hospitalization compared to those with a normal BMI. patients with a BMI ranging between 30 and 39.9 exhibited decreased hospitalization costs when compared to patients with a normal BMI. Moreover, our study revealed a decrease in atrial fibrillation, acute heart failure and acute kidney injury complications following TAVR in patients with above-normal BMI. Despite similar in-hospital mortality across BMI groups, having a BMI of 25 or greater is associated with improved immediate outcomes following TAVR. These benefits in overweight and obese patients are consistent with findings described in recent literature. Further studies are warranted to explore the underlying mechanisms and potential implications of these associations, as well as to optimize patient selection and management strategies for TAVR procedures.

On the existence of low-valent magnesium-calcium complexes.

DFT-Calculations predict that a low-valent complex (BDI)Mg-Ca(BDI) with bulky ß-diketiminate (BDI) ligands is thermodynamically stable. It was attempted to isolate such a complex by salt-metathesis between [(DIPePBDI*)Mg-Na+]2 and [(DIPePBDI)CaI]2 (DIPePBDI = HC[C(Me)N-DIPeP]2; DIPePBDI* = HC[C(tBu)N-DIPeP]2; DIPeP = 2,6-CH(Et)2-phenyl). Whereas in alkane solvents no reaction was observed, salt-metathesis in C6H6 led to immediate C-H activation of benzene to give (DIPePBDI*)MgPh and (DIPePBDI)CaH, the latter crystallizing as a THF-solvated dimer [(DIPePBDI)CaH·THF]2. Calculations suggest reduction and insertion of benzene in the Mg-Ca bond. The activation enthalpy for the subsequent decomposition of C6H62- into Ph- and H- is only 14.4 kcal mol-1. Repeating this reaction in the presence of naphthalene or anthracene led to heterobimetallic complexes in which naphthalene2- or anthracene2- anions are sandwiched between (DIPePBDI*)Mg+ and (DIPePBDI)Ca+ cations. These complexes slowly decompose to their homometallic counterparts and further decomposition products. Complexes in which naphthalene2- or anthracene2- anions are sandwiched between two (DIPePBDI)Ca+ cations were isolated. The low-valent complex (DIPePBDI*)Mg-Ca(DIPePBDI) could not be isolated due to its high reactivity. There is, however, strong evidence that this heterobimetallic compound is a fleeting intermediate.

A Versatile Prison Psychiatric Pharmacy Program.

BACKGROUND: Before the coronavirus disease 2019 (COVID-19) pandemic, 20% of the adult population in the United States experienced mental illness annually. Since the COVID-19 pandemic, 93% of countries have reported disruptions to mental health services. The demand for services is high whereas infrastructure and qualified professionals are appallingly low. Health care in the correctional setting is unique, where mental illness prevalence is double than that in the community. The intersection of policies and procedures and the beneficence plus nonmaleficence responsibility of health care professionals is exceptionally complex. Studies have shown the potential benefits of pharmacists following patients in chronic care psychiatry visits. OBJECTIVES: An inpatient psychiatric pharmacy clinic was launched to fill gaps to provide safe and up-to-date patient-centric services for more than 240 extremely psychiatrically ill inmate patients at the Federal Correctional Center Butner (FCC Butner), a Federal Bureau of Prisons medical center. METHODS: The inpatient psychiatric pharmacist practiced independently under a collaborative practice agreement and completed mental health clinical visits for a revolving portion of 240 inpatient mental health inmate patients at FCC Butner. The pharmacist provided ancillary services including completing movement disorder testing, monitoring narrow therapeutic index medication laboratory test results, and executing an antipsychotic psychoeducation meeting with other health care departments and inmate patients. RESULTS: Notably, 74% of patients monitored in the specialty program experienced stable or improved symptoms of depression, schizophrenia, and bipolar disorder. Adverse effects, particularly psychiatric-related movement disorders, were also more closely managed. Finally, 43% of the total inmate patient population who previously declined psychiatric medication treatment consented to begin treatment after participation in a pilot antipsychotic psychoeducation meeting. CONCLUSION: The inpatient psychiatric pharmacy program at FCC Butner is a dynamic program that has bolstered the facility's health care mission. The services detailed in this article can be applied to other correctional environments that have a medical outpatient or inpatient presence.

Long-term Outcomes Following a Comprehensive Quality Assurance and Process Improvement Endeavor to Minimize Opioid Use After Kidney Transplant.

Importance: Opioid use following kidney transplant is associated with an increased risk of graft loss and mortality. Opioid minimization strategies and protocols have shown reductions in short-term opioid use after kidney transplant. Objective: To evaluate the long-term outcomes associated with an opioid minimization protocol following kidney transplant. Design, Setting, and Participants: This single-center quality improvement study evaluated postoperative and long-term opioid use before and after the implementation of a multidisciplinary, multimodal pain regimen and education process in adult kidney graft recipients from August 1, 2017, through June 30, 2020. Patient data were collected from a retrospective chart review. Exposures: Preprotocol and postprotocol implementation use of opioids. Main Outcomes and Measures: Between November 7 and 23, 2022, opioid use before and after protocol implementation was evaluated up to 1 year after transplant using multivariable linear and logistic regression. Results: A total of 743 patients were included, with 245 patients in the preprotocol group (39.2% female and 60.8% male; mean [SD] age, 52.8 [13.1 years]) vs 498 in the postprotocol group (45.4% female and 54.6% male; mean [SD] age, 52.4 [12.9 years]). The total morphine milligram equivalents (MME) in the 1-year follow-up in the preprotocol group was 1203.7 vs 581.9 in the postprotocol group. In the postprotocol group, 313 patients (62.9%) had 0 MME in the 1-year follow-up vs 7 (2.9%) in the preprotocol group (odds ratio [OR], 57.52; 95% CI, 26.55-124.65). Patients in the postprotocol group had 99% lower odds of filling more than 100 MME in the 1-year follow-up (adjusted OR, 0.01; 95% CI, 0.01-0.02; P < .001). Opioid-naive patients postprotocol were one-half as likely to become long-term opioid users vs preprotocol (OR, 0.44; 95% CI, 0.20-0.98; P = .04). Conclusions and Relevance: The study's findings show a significant reduction in opioid use in kidney graft recipients associated with the implementation of a multimodal opioid-sparing pain protocol.

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation.

OBJECTIVES: LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring. METHODS: This was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele). RESULTS: In this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race. CONCLUSION: CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers.

Statins Restore Endothelial Protection against Complement Activity in Obstructive Sleep Apnea: A Randomized Clinical Trial.

Rationale: Increased cardiovascular risk in obstructive sleep apnea (OSA) persists after continuous positive airway pressure (CPAP) and alternative therapies are needed. Impaired endothelial protection against complement is a cholesterol-dependent process that initiates endothelial inflammation in OSA, which increases cardiovascular risk. Objectives: To investigate directly whether lowering cholesterol improves endothelial protection against complement and its proinflammatory effects in OSA. Methods: Newly diagnosed patients with OSA (n = 87) and OSA-free controls (n = 32) participated. Endothelial cells and blood were collected at baseline, after 4 weeks of CPAP therapy, and again after 4 weeks of 10 mg atorvastatin versus placebo using a randomized, double-blind, parallel-group design. Primary outcome was the proportion of a complement inhibitor, CD59, on the endothelial cell plasma membrane in OSA patients after 4 weeks of statins versus placebo. Secondary outcomes were complement deposition on endothelial cells and circulating levels of its downstream proinflammatory factor, angiopoietin-2, after statins versus placebo. Results: Baseline expression of CD59 was lower, whereas complement deposition on endothelial cells and levels of angiopoietin-2 were greater, in patients with OSA compared with controls. CPAP did not affect expression of CD59 or complement deposition on endothelial cells in patients with OSA, regardless of adherence. Compared with placebo, statins increased expression of endothelial complement protector CD59 and lowered complement deposition in patients with OSA. Good CPAP adherence was associated with increased angiopoietin-2 levels, which was reversed by statins. Conclusions: Statins restore endothelial protection against complement and reduce its downstream proinflammatory effects, suggesting a potential approach to reduce residual cardiovascular risk after CPAP in patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT03122639).